The compounds of this invention inhibit the action of the hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma .alpha.2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by ACE to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. Administration of a compound of this invention with a diuretic such as furosemide or hydrochlorothiazide, either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound. Administration of a compound of this invention with a NSAID can prevent renal failure which sometimes results from administration of a NSAID.
Several peptide analogs of AII are known to inhibit the effects of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by their partial agonist activity and lack of oral absorption (M. Antonaccio, Clin. Exp. Hypertens., 1982, A4, 27-46; D. H. P. Streeten and G. H. Anderson, Jr.--Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed., A. E. Doyle, Vol. 5, pages 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984).
Several non-peptide antagonists of angiotensin II, including some biphenylmethyl imidazoles, have been disclosed. U.S. Pat. Nos. 5,137,902 and 5,138,069 disclose biphenylmethylimidazoles (A) where R.sup.1 may be a ##STR2## phenyl substituted in the 2'-position with acidic functional groups, such as carboxy, --CONHSO.sub.2 R and tetrazole, and where R.sup.8 may be formyl, acyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkoxyalkyl and hydroxyalky. PCI publication WO 91-00277 and Ser. No. 07/900,540 now U.S. Pat. No. 5,254,546 disclose substituted imidazoles of the same basic structure where R.sup.7 may be optionally substituted aryl or heteroaryl. European Application EP 479,479 (Merck) discloses biphenylmethyl imidazoles (B) where R.sub.1 B may represent alkyl, R.sup.3 may be H, alkyl, alkenyl or alkynyl, perfluoroalkyl, halogen, NO.sub.2, CN or optionally substituted phenyl, R.sup.4 includes formyl, acyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkoxyalkyl and hydroxyalkyl, X may be a single bond, and R.sup.5 includes --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.12 and --SO.sub.2 NHCONR.sup.2 R.sup.12, in which R.sup.2 is H or alkyl, and R.sup.12 is aryl, heteroaryl, cycloalkyl, perfluoroalkyl or optionally substituted C1-C4 alkyl, where the alkyl substituents include aryl, heteroaryl, alkyl, OH, SH, alkoxy, thioalkoxy, halo, carboxy, alkoxycarbonyl, NO.sub.2, optionally substituted amino and various phosphoryl radicals.
European Application Number 90305850.1 (EP 400,974) discloses imidazo-fused 6-membered heterocycles (C) as angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure, where A, B, C, ##STR3## and C are independently carbon or nitrogen atoms.
Australian Application AU-A-80163/91 (EP 465,368, Roussel-Uclaf) discloses substituted imidazoles (D) where R.sup.1 may be alkyl, m may be 1, either R.sup.2 or R.sup.3 is OR.sup.4 or a sulfurous group of structure --S(O).sub.nR.sup.4, ##STR4## --SO(R4)=NS(O)nX' or --SSR4, where R4 represents a variety of optionally substituted alkyl, alkenyl, alkynyl, acyl or nitrogenous or sulfurous radicals. The imidazole nitrogen substituent (CH.sub.2).sub.m -Y may represent a biphenylmethyl group, which may be substituted in the 2'-position by acidic groups, such as --(CH.sub.2).sub.m1 --S(O).sub.m2 --X-- R.sup.10, in which m1 may be 0-4, m2 may be 0-2, X may be a single bond, --NH--, --NH--CO--, or --NH--CO--NH-- and R.sup.10 is an optionally substituted alkyl, alkenyl, aryl or heteroaryl radical.
None of the references describe the compounds of this invention.
It is well known that two types of angiotensin II receptors are widely distributed in various mammalian tissues (P. C. Wong et al., Cardiovascular Drug Reviews 1991; 9: 317-339; Trends in Endocrinol. Metab. 1992; 3: 211-217). The angiotensin II receptor most directly involved in the mediation of blood pressure is termed the AT.sub.1 receptor, and is characterized by high sensitivity to the non-peptide antagonist DuP 753. A second angiotensin II receptor, designated AT.sub.2, is sensitive to another class of non-peptide AII antagonists, represented by PD123177 (ibid.), and CGP42112A. Angiotensin II has approximately equal affinity for both receptor subtypes.
Recent evidence suggests that the AT.sub.2 receptor may have a role in mediating the synthesis and breakdown of cardiac connective tissues. For example, Matsubara et ##STR5## al. (The FASEB Journal 6, 4: A941, 1992) have reported that PD123177, but not DuP 753, blocks the AII-stimulated inhibition of collagenase in cultured cardiac fibroblasts. Both PD123177 and DuP 753 are reported by Zhou et al. to block the AII-stimulated increase in collagen synthesis in cardiac fibroblasts (The FASEB Journal 6, 4: A1914, 1992).
Tsutsumi and Saavedra have found AT.sub.2 receptors in cerebral arteries (Am. J. Physiol. 261: H667-H670, 1991). An analog of PD123177, PD123319, has been reported by Brix and Haberl (The FASEB Journal 6, 4: A1264, 1992) to block the pial artery dilation induced by angiotensin II in a rat cranial window preparation monitored by intravital microscopy. This suggests that the AT.sub.2 receptor may have a role in modifying cerebral blood flow.
The AT.sub.2 selective antagonist CGP42112A has been reported by LeNoble et al. (The FASEB Journal 6, 4: A937, 1992) to block the increase in microvascular density induced by angiotensin II in the chick chorioallantoic membrane, suggesting that angiotensin II may in some contexts mediate angiogenesis through AT.sub.2 receptors.
As noted above, DuP 753, disclosed in U.S. Pat. No. 5,138,069, is a selective AT.sub.1 antagonist, having extremely low affinity for the AT.sub.2 receptor. No data is presented in U.S. Pat. No. 5,138,069 or the other references above which suggests that any of the compounds disclosed possess high AT.sub.2 affinity.
In addition to potent AT.sub.1 antagonist and antihypertensive properties, the imidazole compounds of the present invention possess potent AT.sub.2 antagonist properties. Since AT.sub.1 antagonism leads to increased levels of circulating angiotensin II in vivo (Y. Christen et al., Am. J. Hypertension, 1991; 4: 350S-353S), and the AT.sub.2 -mediated consequences, if any, of higher AII levels are unknown, simultaneous AT.sub.1 /AT.sub.2 antagonism may prove desirable during AT.sub.1 -targeted therapy.